Vasoconstrictor-antihistamine composition for the treatment of hypertrophied oral tissue

ABSTRACT

A COMPOSITION IN THE FORM OF A MOUTHWASH OR TOOTHPASTE FOR THE TREATMENT OF HYPERTROPHIED AND HYPERPLASTIC ORAL TISSUE. THE COMPOSITION CONTAINS AS ESSENTIAL INGREDIENTS THEREOF ONE OR MORE ALKALOIDS, SUCH AS THE SYMPATHOMIMETIC AMINES, WHICH ARE VASOCONSTRICTORS AND EFFECT VASOCONSTRICTION OF THE ORAL TISSUE AND AN ANTIHISTAMINIC AGENT WHICH INTERFERS WITH THE ACCESS OF HISTAMINE TO THE ENDOTHELIAL CELLS OF THE CAPILLARY MEMBRANE.

States Patent ice 3,822,349 Patented July 2, 1974 US. Cl. 424-54 9 Claims ABSTRACT OF THE DISCLOSURE A composition in the form of a mouthwash or toothpaste for the treatment of hypertrophied and hyperplastic oral tissue. The composition contains as essential ingredients thereof one or more alkaloids, such as the sympathomimetic amines, which are vasoconstrictors and effect vasoconstriction of the oral tissue and an antihistaminic agent which inter-fers with the access of histamine to the endothelial cells of the capillary membrane.

RELATED APPLICATIONS This application is a continuation-in-part of my copending application Ser. No. 829,793, filed July 2, 1969, now Pat. No. 3,574,859, entitled Process for the Treatment of Hypertrophied Gums which application is a continuation-in-part of my application Ser. No. 742,535, filed July 5, 1968, now abandoned.

BACKGROUND OF THE INVENTION Ahnost all practicing dentists and most physicians, especially those in the field of neurology, otopharyngology, allergy, internal medicine, and related specialties have at one time or another in the normal course of their practice encountered patients exhibiting hypertrophy or hyperplasia of the oral tissue. Enlargement in the size of the oral tissue can be produced either by hypertrophy (increase in the size of each cell) or by hyperplasia (increase in the number of cells) or by both phenomena together. It is usually diflicult to differentiate clinically whether tissue is enlarged from hypertrophy or hyperplasia or both, and for this reason the terms are used often interchangeably. Only microscopically may the differentiation be made.

From a clinical point of view, causes of oral tissue enlargement can be considered of two general types of tissue and may be termed inflammatory hyperplasia and fibrous hyperplasia. At the onset of the enlargement there is usually a true inflammatory swelling which microscopically appears as granulation tissue containing varying amounts of polymorphonuclear leucocytes. If the hyperplastic process persists, there is differentiation and proliferation of tissue cells with result increase in size or in number of cells; fibrosis of tissue usually takes place, the fibroblasts multiply rapidly, connective tissue is formed, the inflammatory cells disappear and finally the tissue becomes characteristic of dense, avascular tissue. Clinically this transition is characterized by decreasing hyperemia and advancing induration of the hyperplastic tissue. The schematic representation of the pathologic process in transition from initiation of inflammation to fibrosis may be illustrated inflammation inflammatory hyperplastia fibrous hyperplasia-efibrosis The chief distinguishing clinical and microscopic signs between the above stages are:

Inflammation is characterized with immediate dilation response of the capillaries to the chemical or physical irritants and the resultant changes in capillary physiology, with increase in the number of open and dilated capillaries supplying the area and increase in capillary filtration of fluids. This stage exhibits no cellular change nor increase in size of the tissue and is the beginning of edema. Microscopically, there is increase in number of leucocytes, especially polymorphonuclear neutrophils, in the tissue fluid with no change in the cellular configuration.

Inflammatory hyperplasia is characterized with soft, hyperemic, edematous, or cyanotic, sensitive to touch, bleeding easily tissues which are beginning to enlarge in size clinically. Microscopically, this condition shows an increase in the number of polymorphonuclear nutrophils and increase in size or number of cells. The number of open or dialated capillaries is also increased. The main feature of this condition is the increase in size of the tissue which is usually not present at the beginning of inflammation.

In fibrous hyperplasia the enlarged tissue is firm, dense, insensitive, resilient, and clinically shows granular appearance. Microscopically, the fibrous tissue is well di-fferentiated with many young fibroblasts present. There is decreased in number of polymorphonuclear neutrophils and open capillaries; the epithelium is slightly hyperplastic and mildly hyperkeratous and hornified. Lamina propria, the su'bmucous layel below the epithelium, shows proliferation of the fibroblasts among which inflammatory cells are present.

Fibrosis is a condition characterized with firm, nodular, fibrous connective tissue. Microscopically, the picture is one of avascular, extremely diflerentiated bundles of fibrous material with no inflammatory cells or open capillary present, or very few at best, in the tissues.

It becomes apparent now that inflammation and hyperplasia or hypertrophy are diiferent and distinct conditions with inflammation at times, especially at the onset of the pathologic process, being associated with hyperplasia or hypertrophy, inflammation being secondary to hyperplasia or hypertrophy. Hyperplasia or hypertrophy is always manifested in enlargement of tissue whereas inflammation may or may not, and usually is not at the beginning stages,be manifested in enlarged tissues.

Hyperplasia or hypertrophy of the oral tissue may vary in degree from a slight increase in tissue bulk to definitely disfiguring enlargement, and may be grouped into three classes: (1) small enlargement associated with some local irritations on tissues predisposed to fibrous poliferetion, (2) idiopathic fibrous hyperplasia, and (3) those caused by local application or systemic intake of drugs or other chemical agents, such as diphenylhydantoin.

CAUSES OF ORAL TISSUE ENLARGEMENT A. Local Inflammatory, Irritating and Traumatic Factors 1. Poor oral hygiene, accumulations of calculus 2. Malphosed teeth, faulty contact points 3. Unusual toothbrush habits 4. Occlusal overfunction 5. Irritation from ill-fitting crowns, clasps, prosthetic or orthodontic appliances b. Menstration and pregnancy 0. Hypothyroidism and pituitary disfunction d. Diabetes e. Gonadal disturbances 2. Nutritional a. Scurvy b. Subclinical nutritional deficiencies of mixed types, in-

cluding B complex 3. Blood dyscrasias a. The leukemiasparticularly monocytic and rnyelogenous b. Polycythemia vera c. Cooleys amenia 4. Drugs a. Diphenylhydantoin (Dilantin) sodium b. Barbiturates 5. Idiopathic forms a. Diffuse fibromatosis of the gums C. Post Extraction Swelling Hypertrophic or hyperplastic oral tissue may be confined to one part of the mouth, such as in the case of post extraction swelling, or it may extend over the entire oral tissue; it may be confined to the gingival margin or enlarge to the extent of the entire oral cavity tissue from the gingiva to the buccal and lingual reflections and to the tonsilar and pharyngeal areas. The initial clinical picture usually exhibits an etiological factor of congestion with edema and hyperemia followed by less of the infiammatory character and thickening and fibrosis of the connective tissue layer if the causes of oral tissue enlargement are allowed to persist.

Many theories have been postulated for the treatment of hyperplasia and hyperthrophy of the oral tissue; treatment ranging from the use of diuretics, steroids, anti-inflammatory agents, and other biochemicals with questionable results. The treatment of choice accepted by most clinicians knowledgeable in the art of periodontology is gingivectomy (surgical excission of the hypertrophied or hyperplastic tissue) if the condition is not too severe and complete clearance of teeth (full mouth extraction) if the enlarged tissue interferes with patients mastication. Heretofore there is no known therapeutic treatment for the cure or control of hyperplasia or hypertrophy, whether associated with diphenylhydantoin sodium or other irritating causative factors, and surgical excission of the enlarged tissue around the teeth is about the only reliable treatment; however, recurrence of hyperplasia or hypertrophy of the oral tissue is certain to reappear after a few months. Complete clearance of the teeth is necessary if the condition is severe. This invention relates to a process and composition for treatment of the enlarged oral tissue which has not been suggested before and is novel in its pharmacodynamic action on the enlarged tissue.

The mode of diphenylhydantoin sodium action on the enlarged tissue is diversified and complicated and certain cytologic actions are not clearly elucidated. However, the resultant enlargement of the oral tissue due to this drug is similar clinically to the enlargement caused by other chemical and physical irritants. For this obvious reason the pharmodynamic action of the drug diphenylhydantoin on the oral tissue is emphasized in this patent application but in no way it should restrict the use of this invention only to the enlargement caused by this drug.

Many studies have been made in regard to the causal relationship of diphenylhydantoin sodium with oral tissue hyperplasia or hypertrophy and the resultant fibrosis of the said tissues with all investigators agreeing that diphenylhydantoin hyperplasia is essentially the result of irritation of the gingival tissue around the teeth by the drug when taken systemically. Hyperplasia or hypertrophy does not occur in the edentulous areas which indicates that the teeth serve as nodi of diphenyhydantoin sodium irritation. Almost all investigators agree that there is no relationship between the amount of diphenylhydantoin intake and the degree of resultant fibrous hyperplasia. Perhaps this fact indicates that the action of diphenylhydantoin on the tissues works on the all or none principle-even a small amount of diphenylhydantoin will exert the same irritating effect on the tissues or it will not effect the tissues at all. Therefore, some metabolic changes occur at the tissue level that prevents reabsorption of the diphenylhydantoin by the venous circulation and consequent elimination by the kidneys in the urine, making possible the retention of the diphenylhydantoin sodium complex in the intercellular substance to initiate fibrosis. Hypertrophy and hyperplasia of the oral tissues continues to attract interest in the dental profession especially in periodontology, because of the lack of treatment for this condition and the high percent of occurrence in patients under treatment with diphenylhydantoin for the control of convulsive seizures. The overwhelming gingival oral tissue reaction to this drug necessitates more and more efiort on the dental profession to treat this condition as a serious one since heretofore there are no biochemicals available to aleviate this condition therapeutically; only surgical intervention or taking the drug away from the patient; will provide temporary relief. Complete removal of the teeth will usually result in total elimination of this problem.

Local or systemic irritation, be it chemical such as diphenylhydantoin sodium or physical such as faulty dental restorations and prosthesis, will initially start in edema and gradually progress to fibrosis unless there is some sort of therapeutic intervention between the two points to prevent the extreme fibrosis. Edema can, and usually does, precede hypertrophy and hyperplasia and finally fibrosis, but it is not a part of the fibrosis process itself, edema being a condition characterized with unusual accumulation of extravascular fluid in the tissues. The causative factor in production of edema is the apparent imbalance between the transudation of fluid from the circulation and its return by the vascular system. Exchange of water and solutes across the capillary membrane occurs by filtration at the artetiolar end of the capillary bed and reverse flow, or absorption, at the venous end. The two most important factors that influence the rate of fluid and solutes across the capillary membrane are tissue tension and capillary permeability.

Diphenylhydantoin sodium was introduced into medicine for symptomatic treatment of epileptic seizures and has become the drug of choice for treatment and control of convulsive conditions due to its non hypnotic efl'ect on the central nervous system. The primary concern of the dental profession to this drug is the effect it has on the oral gingival tissue causing fibrous proliferation which results in fibrous enlargement of the gums. Gingiva is that portion of the oral mucous membrane which surrounds the teeth and is not attached to the underlying alveolar bone. It differs from the mucous membrane in that the epithelium is thicker and hornified to better resist the constant stresses applied to the tissue during mastication. Once the teeth are removed the gingiva ceases to exist; then it becomes attached to the alveolar bone and the epithelium looses its hornification. Some periodontists hold the gingiva to be different tissue from mucous membrane and this differentiation is particularly true in case of fibrous hyperplasia due to Dilantin since the drug affects only the gingiva, the tissue around the teeth, and has no effect on the rest of the mucous membrane of the mouth.

Diphenylhydantoin sodium when taken orally, in either flavored or oil vehicle, is partially dissolved in the intestine and readily absorbed by the circulation and carried throughout the body, especially in the areas demonstrating high metabolic rate of the tissues such as brain, the hair follicle, the oral gingiva etc. Since the alkalinity of the gastric fluid and of the oral tissues is not high enough to provide complete dissolution of diphenylhydantoin sodium (the pH must be about 11.7 to obtain saturated solution) the unchanged drug, due to its affinity for the tissues in high metabolic rate, findsits way into the extracellular ground substance of the oral gingiva. Once in the ground substance of the gingiva diphenylhydantoin conjugates with glucuronic acida metabolite of hyaluronic acid, and in this form it is excreted in the urine. The metabolites found in the urine are conjugated with glucuronic acid. The conjugation reaction involves combination of a metabolite of diphenylhydantoin with some other substance, such as the metabolite of hyaluronic acidglucuronic acid, followed by the elimination of the resulting conjugate. The dissolved diphenylhydantoin in the ground substance of the oral gingiva is easily dissociated even by weak acids such as carbon dioxide (CO2) which is the biproduct of metabolism in the tissues whenever the tissues are active in response to a chemical or phyical stimulant, with the regeneration of 5,5-diphenylhydantoin. The metabolites of diphenylhydantoin, hydantoic acid and amino acid, by the action of carbon dioxide and the subsequent increase of carbonic acid (H CO are regenerated to the 5,5-diphenylhydantoin which is made available for more conjugation with glucuronic acid and therefore binding in the ground substance of the gingiva. This complex, unless eliminated by the urine, will prolong the irritation of the fibroblasts resulting in secretion of collagen for formation of fibrous tissue bundlles. It now becomes apparent that diphenylhydantoin in the oral tissues undergoes a visous cycle of disassociation and regeneration.

Another important characteristics of diphenylhydantoin action in the gingival tissue is that it stimulates liberation of histamine and histamine-like substances and reduces the amount of serotonin. Histamine is found in the cells of most connective tissue and its primary function upon liberation is to vasodialate the arterioles and capillaries thereby bringing more circulation to the injured area and to lower the capillary permeability. Dipbenylhydantoin in regard to the capillary membrane has dual eifect; initially it stimulates the chemoreseptors of the endothelical cells to secrete histamine and secondly it acts directly on the smooth muscle of the arteries and arterioles causing lowering of membrane permeability. Diphenylhydantoin and nistamine both jointly vasodialate the capillaries and increase the capillary membrane permeability allowing diffusion of not only crystalloids but also colloidal substances from the vacular system and into the tissue spaces. This particular action of diphenylhydantoin, vasodilatation and alteration of capillary membrane permeability, is essentially the reason why edema is preceding or superimposed condition to fibrosis of the gingiva in diphenylhydantoin therapy.

The outer layer of the mucous membrane--the hornified epithelium, is acidophil in character and the underlying submucous layer is alkaline having pH of approximately 7.4. The alkalinity of the submucous layer, where the ground substances are found, maintains the consistency of the hyaluronic acid gel-like and stable. Alkalinity having pH (or more preceisely pOH) of 7.4 is not high enough to keep the diphenylhydantoin sodium present in the tissues in solution but is high enough to prevent disaggregation of hyaluronic acid by the carbonic acid which is produced during tissue metabolism. The viscous consistency of the ground substance keeps the conjugate of the diphenylhydantoin-glucuronic acid bound or captured within the tissue spaces preventing the conjugated complex from being absorbed and subsequently excreted by the venous circulation. Retention of the diphenylhydantoin complex in the ground substance enables the drug to prolong and intensify its stimulatory effect on the fibroblasts resulting in gingival fibrosis.

6 SUMMARY OF THE INVENTION This invention pertains to compositions uniquely suited for the treatment of hypertrophied or hyperplastic tissue and which comprise in combination a vasocontrictiug alkaloid and an antihistamine. The preferred alkaloids for use in this invention are aromatic amines having between about 6 to 10 carbon atoms and aliphatic amines having between about 4 to 7 carbon atoms. The preferred antihistaminics are those of the skeletal structural formula:

XCH,-oH,-N

wherein X may be oxygen, nitrogen or carbon, and R, R and R" are either aryl, alkyl or aralkyl groups.

The antihistamine should have a minimum molecular weight of about 150, and each of the aryl, alkyl or aralkyl groups should contain the range of about 2 to 16 carbon atoms. If X in the structure shown above is nitrogen, the resulting compound may be viewed as an ethyleadiamine derivative; if oxygen, as an aminoalkyl ether; and if carbon as an alkylamine. Attached through the carbon, oxygen or nitrogen is the so-called nucleus of the antihistaminic drug. Preferably, this nucleus should consist of a minimum of two aryl or arlkyl groups.

The compositions of this invention should contain the vasoconstricting alkaloidal and antihistaminic each in an amount of about 00125 to 5.0 percent by weight based on the weight of the entire composition. When the alkaloid is present in an amount in excess of about 1.0 weight percent then the weight ratio of alkaloid to antihistamine is preferably about 1:05, that is, the amount of antihistamine employed is about half that of the alkaloid. When the concentration of alkaloid is less than about 1.0 percent, then good results have been found using an equal amount of the antihistamine, or an alkaloid to antihistamine ratio of 1:1. These ratios are not absolute and are being set forth only as a guide.

DESCRIPTION OF THE PREFERRED EMBODIMENT insulation of the composition of this invention on the oral tissues, for example, either in mouthwash or toothpaste formulations, will readily penetrate the outer keratinous epithelial layer, break the electrical polarization that exists between the acidic epithelium and the alkaline submucosa and diffuse into the deeper submucous tissues. Brushing or masaging of the gum will express the air bubble from the epithelium, particularly the air bubbles in the ducts of the secretory glands which extend deep into the submucosa, providing entrance and facilitate absorption of the drug. Once the drug gains entrance in the ground substance of the enlarged tissue its alkalinity will readily neutralize the acid present during the tissue activity resulting in metabolic alkalosis. This neutralization tends to increase the pH of the tissue fluid from 7.4 to about 10-12, depending on the dissociation of the alkaline composition to free hydroxyl group and the amount of carbonic acid present in the tissues for neutralization. Increased alkalinity of the tissue fluid, especially around pH 1l-12, results in increased dissolution of diphenylhydantoin either in the conjugated or metabolic form, thusly eliminating the drug by the venous capillary system. The change of tissue acidity affects the hydrolysis of ground substance-hyaluranic acid. On hydrolysis, hyaluronic acid yields equimolar amounts of d-glucoseamine, d-glucuronic acid, and acidic acid and is believed to contain a repeating disaccharide unit comprising N- acetyl glucoseamine glucuronide. Hydrolysis of the glucuronic acid decreases the viscosity of the ground substance freeing the diphenylhydantoin portion from the diphenylhydantoin-glucuronic acid conjugate to be dissolved by the alkaline composition, particularly when the pH is 11-12, and subsequently eliminated by the kidneys.

The dissolution of the drug diphenylhydantoin in the tissue fluid will result in decrease of stimulatory effect the drug has on the fibroblasts therefore lessening the chance for fibrosis.

Another important function of this invention, in acid as well as alkaline formulations, is the effect it has on the collagen material of the oral tissues. Collagen is the most abundant protein material in any connective tissue. The fibrous connective tissue contains 63% water, and 31.6% collagen with small amount of elastin and mucoids. Collagen is a tough, inert, insoluble in water fiber but slowly converted to gellatin by boiling water, dilute acids and alkalies. Diphenylhydantoin, being an irritant, stimulates the fibroblasts to secrete collagenous material which is precipitated outside the cells forming interconnected bundles of the insoluble threads. This process of fiber formation is called fibrosis. The acid or alkaline character of my composition will retard the excretion of the collagen material by the fibroblasts (fibroblasts are germinating cells, or precursors, giving rise to new fibers) thusly minimizing, if not completely eliminating the possibility of fibrosis. The acidity, or the alkalinity, of this invention will gradually convert the newly formed collafenous fiber into more easily reactive gelatin which is readily digestable by tissue enzymes and removed by the circulation. The composition of this investion will further gradually break the bonds linking parallel polypeptide chains to single peptide chains of gelatin. The compensatory alkalinity of the tissue fluid during the treatment with the compositions of this invention is opposed by the buffering system of the intercellular fluid and the excess alkalinity will be neutralized by the carbonic acid of the tissue fluid in order to keep the proper bicarbonate/car bonic acid ratio 20:1 at pH 7.4.

The vasoconstrictor component of the compositions of this invention, such as the sympathomimetic amine phenylephrine hydrochloride, upon entrance into the ground substance of the tissue acts directly on the chemoreseptors of the endothelical cells of the capillary membrane. It causes swelling of the cells thereby decreasing the lumen of the capillaries and restoring the patency of the membrane. This vasoconstriction of the arterioles and capillaries (the venuoles are not affected to an appreciable degree) stops the escape, or leakage, of the larger molecules of proteins and the unchanged diphenylhydantoin sodium from the circulation and into the tissues thereby restoring the normal balance of vascular and extravascular fluid and electrolytes exchange. The prevention of diphenylhydantoin escape into the tissues and the subsequent elimination of the metabolites of diphenylhydantoin from the tissues by the venous circulation, reduces the amount of the drug available for stimulation of the fibroblasts to secrete collagenous material and form the insoluble fibers. Decrease of diphenylhydantoin metabolites from the tissues liberates the calcium ions from the complex diphenylhydantoin-calcium conjugate allowing it to return to the cement material of the endothelial cells of the capillary membrane and decreases the liberation of histamine by the stimulated and active cells. The vasoconstriction of the capillaries deprives the hypertrophied or hyperplastic cells from nutrition and subsequent decrease either in the size of the cells themselves or the number of cells. In hypertrophy or hyperplasia, especially at the initial stages, there is increase in the number of capillaries which is evident under microscopic examination. The vasoconstrictor, phenylephrine hydrochloride, by virtue of its action on the endothelial cells of the capillary membrane decreases and sometimes virtually eliminates, particularly the newly formed capillaries, from being able to supply the hypertrophied or hyperplastic cells with nutritious materials therefore practically starving the new cells to death. This event is especially true before fibrosis is allowed to proceed.

The antihistamine, as for example, antazoline hydrochloride, upon entrance into the ground substance of the oral tissues prevents the access of histamine liberated by the excitatory elfect of diphenylhydantoin on the tissue cells, to its receptor site in the endothelial cells of the capillary membrane and thereby blocks the response of the effector cell to the amine. The antihistamine possesses no pharmacodynamic acition; it does not react or have antagonistic action with the histamine. The antihistamine occupies the receptor site of the endothelial cells without causing a cellular response. This characteristic of the antihistamine used in my formulations potentiates the physiological antagonism of the sympathomimetic amine to the effects of the histamine on the capillary membrane resulting in more profound vasoconstriction. The pharmacodynamic action of, for example, the phenylephrine hydrochloride-antazoline hydrochloride combination is more intense than that produced by either agent used alone. Phenylephrine hydrochloride gives a very rapid onset of reduction of local oral tissue swelling while antazoline hydrochloride prolongs the reduction in the size of the oral tissue by its direct action on the capillary membrane.

The most beneficial advantage of vasoconstrictor-antihistamine combination is virtually elimination of any side effects produced by either agent used alone. The sedative effect of the antihistamine will counteract the stimulant effect of the sympathomimetic agent.

In obtaining the new and novel treatment, this invention makes use of certain alkaloid compounds or substances which are sympathomimetic amines, and which possess among other properties those of serving as decongestant or vasoconstrictors effecting shrinkage of the overgrown oral tissues. Preferred are aromatic amines having between six to ten carbon atoms, and aliphatic amines having a total of between four to seven carbon atoms. Some examples of useful compounds are:

A. AROMAIIC NUCLEUS I. Unsubstituted:

1. Phenylethylarnlne CtYR-CHz-CHz-NH:

2. Phenylethanolamine-.. Calh-CHOH-CHz-NH;

3. Amphetamine CuI'Is-CHa-CHCHrNHz 4. Dextro-amphetamlneu Isomer of amphetamine.

5. Methamphetamlne..... GuHs-CHrCHCHz-NHCH;

7. Phenylpropanolamine CQH5-CHIOFLCHCHTNHQ 8. Ephedrlne CtHt-CHOH-CHCHs-NHCH; 9. Naphazoline.

10. lPheinylpropylmethy am ne. II. Monosubstltuted:

1. Tyramine HO'CUHI-CHZ'CHZ'NHi 4. Propylhexedrlne S CHZ'CHCHSNHCH Ephedrine sulfate, phenylephrine hydrochloride, cyclopentamine hydrochloride, methylhexaneamine hydrochloride, and oxymetazolin hydrochloride, are the preferred sympathomimetics because they can be employed in aqueous oil and alcohol solutions and in mixtures thereof.

They are readily available, relatively stable, do not decompose readily to light, heat or air. They can be boiled for sterilization, have a long duration of action and are substantially free of aftercongestion.

The antihistamine employed in the compositions of this invention may be any of the commercially available comcompounds, the majority of which have the structural formula:

in which it is apparent that core of the structure is a substituted ethylamine, which is also present histamine. It is most likely that it is this portion of the molecule which completes with histamine for cell receptors. In most intances, the ethylamine grouping is present as a straight chain, but in a few it is part of a ring structure.

Nearly always, the substituted ethylamine of histamine antogonists is teritary, with the activity of secondary or primary amines being greatly attenuated. Furthermore, optimal substituent groups on the amine in most senses is N-dimethylalkyl. Generally N-diethyl compounds are less active and more toxic. Occasionally, the substituted amine is incorporated in a heterocyclic ring Without loss of activity. Quartenization of the tertiary amine diminishes but does not abolish activity.

As noted earlier in this application, X- in the structure may be oxygen, nitrogen or carbon and it is not possible to make any great distinction between these with respect to antihistaminic activity. In addition, the following can be associated with antihistaminic activity: aminoketones, secondary aminoalcohols, alkylesters and haloalkylamines.

Attached through the carbon, oxygen or nitrogen is the so-called nucleus of the antihistamines which should consist of a minimum of two aryl or aralkyl groups or their equivalent in a polycyclic ring system, with the nucleus having a minimum molecular weight of 150.

Some of the typical antihistamincs are the hydrochlo rides, citrates, maleates and succinates such as:

Antazoline hydrochloride C H N .HCL tripelennamine hydrochloride C H N .HCL Tripelennamine citrate C16Hg1N3.(C HOq)2 Thonzylamine hydrochloride C H 'CLN QHCL Methapyriline hydrochloride C H N S.HCL Methapheniline hydrochloride C H N S.HCL Pyrilamine maleate C H N O.C H O Chlorphenamine maleate" C H CLN .C H O Chlorothen a C H CLN S Pheniramine C H N Pheniramine maleate -C H N .C H O Chlorcyclizine hydrochloride C H CLN HOL Diphenhydramine hydrochloride C17H21NO.HcL Doxylamine succinate C H N O Phenyltoloxamine citrate C H NO Diphenylpyraline hydrochloride C H NO.HCL Phenindamine tartrate C H N Thenyldiamine hydrochloride C H N S Antazoline hydrochloride, diphenhydramine hydrochloride thonzylamine hydrochloride, and chlorphenamine maleate are the preferred antihistaminics in this invention due to their lack of incidence of side action and low tissue irritancy; however, any of the above named antihistaminics may be used in this invention without lowering the potency and the effectiveness of the fluid and toothpaste compositions.

The following examples illustrate mouthwash and toothpaste compositions of this invention.

EXAMPLE 1 (a) Each cc. of a 1.0% mouthwash composition contains:

The pH of the solution is adjusted between 7.0 and 12.0 by the addition of sodium hydroxide.

EXAMPLE 2 Each cc. of a 1.0 percent mouthwash composition contains: The same ingredients in the same amounts and concentrations as in Example 1 except the pH is adjusted between 2.0 and 7.0 with the addition of phosphoric acid. 'Other acidic materials such as citric acid could be used.

In Examples 1 and 2 10.00 mg. of phenylephrine hydrochloride U.S.P., and 5.00 mg. of antazoline hydrochloride U.S.P., were dissolved in 120 cc. of alcohol. The premeasured amounts of benzalconium chloride, saccharine sodium, sodium chloride, spearmint oil, and the preservative sodium thiosulfate were added to the solution before the pH was adjusted to the desired range. In Example I, where the pH should be between 7 and 12, the sodium hydroxide must be added when the alkaloids, phenylephrine hydrochloride and antazoline hydrochloride, are dissolved in alcohol to prevent precipitation of the alkaloids by the alkaline sodium hydroxide. Addition of at least 10% alcohol to composition will prevent the precipitate from forming.

EXAMPLE 3 Each cc. of a toothpaste composition contains:

The pH was adjusted between 7 and 12 with sodium hydroxide. Other alkaline materials such as sodium carbonate or sodium acetate could be used for this purpose.

EXAMPLE 4 Each 90 cc. of a 1.0% of the toothpaste composition contains: The same ingredient in the same amounts and concentrations as in Example 3 except the pH is adjusted between 2.0 and 7.0 with phosphoric acid or citric acid.

In the toothpaste composition the addition of the alkaline sodium hydroxide or sodium acetate will not result in precipitate formation with the alkaloids, phenylephrine hydrochloride and antazoline hydrochloride, due to presence of glycerol and propylene glycol of more than 10.0% of the total composition. Glycerol and propylene glycol have the characteristic of preventing precipitate formation between alkaloids and alkalines, as does alcohol in Example I.

Seven patients undergoing treatment with diphenylhydantoin sodium for control of epilepsy, were treated with their consent with the above described mouthwash and toothpaste compositions by the inventor, Carl M. Kosti, D.D.S. All seven patients exhibited the clinical evidence of gingival hypertrophy or hyperplasia: the enlarged tissue was sore and bleeding at certain areas of the oral cavity of all seven patients with fibrosis present in one patient that has been under treatment with /2 grains of diphenylhydantoin sodium two to three times a day for several years. Three patients were treated with the fluid composition of the invention and four patients with the toothpaste composition of the invention. The patients using the fluid composition were instructed to swish or gargle 15 to 25 cc. of the mouthwash for approximately one to two minutes and to expel the remainder. The patients using the toothpaste composition were instructed to express approximately one inch of the toothpaste on a soft or medium hard toothbrush and gently massage the gums, particularly the affected areas, for about one to two minutes and expel the remainder. All seven patients were discouraged to rinse the mouth after usage of either the mouthwash or the toothpaste composition for approximately one hour for better absorption of the active ingredients by the oral tissue. The procedure was repeated three to four times a day for ten consecutive days with clinical observation and measurement of the depth of the sulci at the affected areas each day. At the end of the ten day clinical trial all seven patients showed marked improvement in appearance and oral comfort. The oral tissues were no longer painful and bleeding when brushed, hypertrophied or edematous; the patients were able to brush their teeth without fear of pain and the mastication was normal, without pain or bleeding.

In Example 3, in addition to phenylephrine hydrochloride, the vasoconstricting sympathomimetic amine, glycerin is used as a sweetening agent or vehicle in place of syrups (syrups are contraindicated in toothpaste due to their high carbohydrate content increasing the incidence of tooth decay) and to maintain the consistency of the toothpaste; propylene glycol is used in my formulation as a diluent and binder and may serve as a substitute for glycerin and alcohol; methylparaben is used as a preservative due to its inhibitory action on the microorganisms; saccharine sodium solution is used as a sweetening agent; peppermint oil is one of the many essential oils that can be used as flavoring agents; mineral oil in my invention is used as a diluent; sodium lauryl sulfate is used as an emulsifier and foaming agent; dicalcium phosphate, due to its fineness is employed as an abrasive; sodium carboxymethylcellulose is used as an emulsifier and thickening and suspending agent; and distilled water in the context of my invention is used as a vehicle and dilutant.

EXAMPLE 5 A toothpaste was prepared as in Example 3 with the addition of the following ingredient:

Stannous fluoride--1 p.p.rn. (one part per million) Stannous fluoride and other fluoride derivatives such as sodium fluoride, monofluorophosphate, potassium fluoride, etc. are elfective anticariogenic substances used in toothpaste to control tooth decay by their action on the protein portion of the enamel and dentin making the said protein portions harder and subsequently more resistent to acid desolution and bacterial invasion. Such substances are generally used in concentrations of 0.25 to p.p.rn.

Other preservatives and their concentrations that can be used in lieu of methylparaben in the context of my invention are:

Weight percent Sodium bisul'fite 0.05-0.25 Sodium benzoate 0.05-0.25 Sodium thiosulfate 0.01-0.20 Chlorobutanol 0.01-1.0 Thimerosal 0.001-0.01 Phenylmercuric acetate 0.001-0.01

benzalkonium chloride 1 benzethonium chloride 1 thonzonium bromide sulfocolaurate dioctyl sodium sulfosuccinate sodium alkyl sulfoacetate sodium lauryl sarcocinate cetyl pyridinium chloride 1 sodium tetradecyl sulfate The essential components of the toothpaste composition of this invention are the alkaloid and the antihistamine each in a concentration of from about 0.0125 to 0.5 weight percent, an alkaloid preservative in an amount from about 0.001 to 0.5 weight percent, a suspending agent in an amount of about 0.002 to 2.0 weight percent and from about 1 to Z1 weight percent of a moisture retainer, with the balance of the composition being water.

Suitable compounds for use as the alkaloid preservative are methylparaben, propylparaben, sodium bisulfate, sodium benzoate, sodium thiosulfate, chlorobutanol, thimersol and henylmercuric acetate. Preferred suspending agent materials are sodium carboxymethylcellulose, methylcellulose, bentonite, acacia, sterculia gum and tragacanth. Preferred moisture retainer materials are glycerin, propylene glycol, sorbital, polyethylene glycol, diethylene glycol monoethyl ether, polysorbate, monolaurate and polyoxyethylene sorbitan.

While the toothpaste composition of this invention need only employ the alkaloid, antihistamine preservative, suspending agent and moisture retainer components, excellent results have been obtained from a more balanced toothpaste formulation which included, in addition to the above components, from about 0.01 to 0.5 weight percent of a sweetening agent, about 0.01 to 1.5 of a foaming agent and about 30 to 65 weight percent of an abrasive.

Examples of abrasive materials which can be used in this invent-ion are pumice, calcium carbonate, stannic oxide, dibasic calcium phosphate, magnesium carbonate and tribasic calcium phosphate. Suitable sweeteners include sodium cyclamate calcium cyclamate, saccharines and sodium saccharine. Suitable foaming agents include sodium lauryl sulfate, sodium tetradecyl sulfate, sodium lauryl sareocin'ate, dioctyl sodium sulfosuccinate sulfocolaurate, thonzonium bromide, methyl benzathonium chloride, dichlorobenzalkonium chloride, dichlorobenzathonium chloride, and cetyl pyridinum chloride.

Because the vasoconstrictor-antihistamine combination of this invention has a long duration of action, administration in the morning and at bedtime is generally recommended. Some patients may require treatment more frequently, especially where hypertrophy or hyperplasia or tissue enlargement is of severe nature or where more rapid reduction in size of tissue is indicated. In that case typical application of the drug three times a day is suggested: in the morning, at noon, and at bedtime.

The suggested dosage of the vasoconstrictor is between 0.0125% and 5% and that of the antihistamine ranges from one half to equal concentration of the vasoconstrictor employed. The ratio of vasoconstrictor to antihistamine in a typical example of this invention is either 1:0.5 or 1:1.

1 These compounds are preferably not used in same formulatlons with other soaps and detergents. They are cationic surface active agents and in solution inactivate anionic surface active agents, for example soaps and detergents such as sodium lauryl sulfate. These compounds are also mildly antiseptic and bacteriostatic. Hence, they can be used where a preservative is employed.

1 3 The recommended dosages of the vasoconstrictors are: For adults and children over six years of age:

Severe hypertrophy or enlargement Percent Fluid composition 0.5-2.5 Paste composition 1.0-5.0

Mild to moderate hypertrophy or enlargement Percent Fluid composition 0.125-0.5 Paste composition 0.25 0.75

Daily oral hygiene and prophylaxis Percent Fluid composition .015-01125 Paste composition 0015-01125 For children six years of age or younger:

Severe hypertrophy or enlargement Percent Fluid composition 0.0 1250.25 lPaste composition 0. 05 0.'25

Mild to moderate hypertrophy or enlargement Percent Fluid composition 00125-0025 lPaste composition 0.0125-0.125

Daily oral hygiene and prophylaxis Not generally recommended These concentrations of the vasoconstrictor are only by way of example and recommended dosage and do not limit the percentage concentrations Within the limits of the given examples. People knowledgeable in the arts of compounding pharmaceuticals may with few trials arrive to a preferred concentration of the active ingredients falling within the range of 0.0125% and up to 5%.

The use of sympathominetic amines in combinations with antihistaminic agents for treatment of hyperplastic or hypertrophied and enlarged tissue has never been suggested or implied before; the mode of action of this combination is different than that obtained from either agent used alone. While the sympathomimetic amines have pharmacodynamic action on the chemoreceptors of the endothelial cells of the capillary membranes resulting in a physiological antagonism of the effects of the histamine on the effector cells, the antihistamines prevent the access of histamine to its receptor site in the cells by competative inhibition without causing a cellular response or chemical reaction or antagonism between the histamine and the antihistaminic agent. Further, vasconstrictor-antihistamine combination employed in this patent virtually eliminates any side effect produced by either agent used alone; the sedative effect of the antihistaminic agent will counteract the stimulant effect of the vasocon'strictor. Finally, I am not aware of employing vasoconstrictor-antihistamine combination in high acid or high alkaline pH as described herein due to the precipitation of the alkaloids and the antihistamines, by the alkaline compounds; however, I have discovered that concentration of more than of alcohol or glycols such as glycerin or propylene glycol, will prevent the said precipitation in either the fluid or paste compositions.

This invention has been described in detail with particular reference to preferred embodiments thereof, but it will be understood that variations and modifications can be effected within the spirit and scope of the invention. The disclosure therein is by way of example and in- 14 cluded in the invention are all modifications and equivalents falling Within the scope of the appended claims.

I claim:

1. A composition for the treatment of hypertrophied or hyperpl'astic oral tissue comprising an alkaloid selected from the group consisting of aromatic amines having between about 6 to 10 carbon atoms and aliphatic amines having between about 4 to 7 carbon atoms, and an antihistaminic component selected from the group consisting of antazoline hydrochloride, tripelennamine hydrochloride, tripelennamine citrate, thonzylamine hydrochloride, methapyriline hydrochloride, methapheniline hydrochloride, pyrilamine maleate, chlorphenamine maleate, chlo rothen, pheniramine, pheniramine maleate, chlorcycl-izine hydrochloride, diphenhydramine hydrochloride, doxylamine succinate, phenyltoloxamine citrate, diphenylpyraline hydrochloride, phenindamine tartrate and thenyldiamine hydrochloride and said alkaloid and .antihistaminic compounds each being present in said composition in an amount of from about 0.0125 to 5.0 per cent by weight of the composition.

2. A composition according to claim 1 wherein said alkaloid is selected from the group consisting of ephedrine sulfate, phenylephrene hydrochloride, cyclopentamine hydrochloride, methylhexaneamine hydrochloride, propylhexedrine hydrochloride, oxymetazoline hydrochloride, phenylpropanolamine hydrochloride, and mixtures thereof.

3. :A composition according to claim 1 further including from about 0.001 to 0.5 weight percent of a preservative selected from the group consisting of methylpar-aben, propylparaben, sodium bisulfite, sodium benzoate, sodium thiosulfate, chlorobutanol, themerosal and phenylmercuric acetate.

4. A mouthwash composition according to claim 3 comprising an aqueous solution of said alkaloid, antihistaminic compound and preservative.

5. A toothpaste composition according to claim 1 comprising said alkaloid and said antihistaminic compounds, from about 01001 to 0.5 percent of a preservative, from about 0.002 to 2.0 percent of a suspending agent and from about 1 to 231 percent of a moisture retainer, the remainder of said composition being water and said percentages being based on the weight of the total composition.

6. A toothpaste composition according to claim 5 wherein said suspending agent is selected from the group consisting of sodium carboxymethylcellulose, rnethylcellulose, bentonite, acacia, sterculia gum and tragacanth.

7. A toothpaste composition according to claim 5 wherein said moisture retainer is selected from the group consisting of glycerin, propylene glycol, sor-bital, polyethylene glycol, diethylene glycol monoethyl ether, polysorbate, monolaurate and polyoxyethylene sorbitan.

8. A toothpaste composition according to claim 5 further including from about 0.01 to 0.5 weight percent of a sweetening agent selected from the group consisting of sodium cyclamate, calcium cyclamate, saccharine and sodium saccharine, from about 0.01 to 1.5 weight percent of a foaming agent selected from the group consisting of sodium lauryl sulfate, sodium tetradecyl sulfate, sodium lauryl sarconcinate, dioctyl sodium sulfosuccinate, sulfocolaurate, thonzonium bromide, methyl benzathonium chloride, dichlorobenzalkonium chloride, dichlorobenzathonium chloride, and cetyl pyridinium chloride and from about 30 to 65 weight percent of an abrasive selected from the group consisting of pumice, calcium carbonate, stannic oxide, d-ibasic calcium phosphate, magnesium carbon-ate and tribasic calcium phosphate.

15 16 9. A treatment for tissue which is hypertrophied or hy- OTHER REFERENCES perplastic comprising applying to the area to be treated the composition of claim 1. Chemzcal Abstracts, Vol. 65, entry 9535c, 1966.

R f n s Cited r RICHARD L. HUiPF, Primary Examiner 0 UNITED STATES PATENTS CL 3,574,859 4/1971 KOSti 424-3B0 3 30; 4 24 27,

3,514,513 5/1970 Bechtold '42'454 

